Hemorrhagic areas as a histological prognosticator in oral cancer: A novel proposition.

Determination of prognosis in oncology practice is a major challenge and many histological prognosticators have been applied because of the ease and simplicity of using them in day-to-day practice. Our histopathologic observation on 96 oral squamous cell carcinoma (OSCC) specimens revealed 34 cases associated with frank hemorrhagic areas, which were close to tumor cells. Hence, we propose that there could be a cross-talk between tumor cells and RBCs which can modulate the biological behavior of the tumor and prognosis of the patient. In the present paper, a scientific foundation is provided for this proposition. Furthermore, an experimental approach is recommended which will facilitate the identification of extracellular metabolites within the tumor microenvironment near RBCs. Such studies may pave the way for a better understanding of the clinical heterogeneity of oral cancer due to differential heme content of red blood cells (RBCs) in the tumor microenvironment (TME).

EMMPRIN/BASIGIN as a biological modulator of oral cancer and COVID-19 interaction: Novel propositions.

Extracellular matrix metalloproteinase inducer (EMMPRIN), which is also called BASIGIN/CD147, is a cell surface glycoprotein that belongs to the immunoglobulin superfamily and plays a significant role in intercellular recognition in immunology, cellular differentiation and development. Apart from ACE-2, recently EMMPRIN, has been regarded as a target for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attachment and entry into the host cell. Since one of the routes of entry for the virus is the oral cavity, it becomes imperative to percept oral comorbidities such oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs) in terms of EMMPRIN as a target for SARS-CoV-2. In the present paper, it is proposed that OSCC, by the virtue of upregulation of EMMPRIN expression, increases the susceptibility to coronavirus disease (COVID-19). In turn, COVID-19 in OSCC patients causes exhaustion of EMMPRIN receptor due to binding with 'S' receptor leading to a downregulation of related carcinogenesis events. We proposed that in the ACE-2 depleted situation in OSCC, EMMPRIN receptor might get high jacked by the COVID-19 virus for the entry into the host cells. Apart from the anti-monoclonal antibody, it is recommended to explore the use of grape seed and skin containing mouthwash as an adjunct, which could also have anti EMMPRIN effects in patients with OSCC and OPMDs.

Novel Viewpoints on Tobacco Smoking and COVID-19.

We read with great interest an article by Karanasos et al. titled "Impact of smoking status on disease severity and mortality of hospitalized patients with COVID-19 infection: a systematic review and meta-analysis".1 It is inferred that there is an adverse impact of smoking on disease severity and mortality of hospitalized COVID-19 patients, which is more pronounced in younger patients without diabetes. Literature is flooded with papers on possible interaction and outcome of COVID-19 association with smoking. However, there are still conflicting views on the effect of smoking in patient outcomes. These conclusions are data-driven and lack valid pathogenetic background for interpretation.

Extrachromosomal circular DNAs: an extra piece of evidence to depict tumor heterogeneity.

The tumor microenvironment (TME) comprises a heterogeneous number and type of cellular and noncellular components that vary in the context of molecular, genomic and epigenomic levels. The genotypic diversity and plasticity within cancer cells are known to be affected by genomic instability and genome alterations. Besides genomic instability within the chromosomal linear DNA, an extra factor appears in the form of extrachromosomal circular DNAs (eccDNAs; 2-20 kbp) and microDNAs (200-400 bp). This extra heterogeneity within cancer cells in the form of an abundance of eccDNAs adds another dimension to the expression of procancer players, such as oncoproteins, acting as a driver for cancer cell survival and proliferation. This article reviews research into eccDNAs centering around cancer plasticity and hallmarks, and discusses these facts in light of therapeutics and biomarker development.

Induction of Apoptotic Death and Cell Cycle Arrest in HeLa Cells by Extracellular Factors of Breast Cancer Cells

Background: There are evidences on the role of extracellular factors in cellular communication between cancer cells and non-cancerous cells to support tumor progression and a phenomenon of cancer cachexia. However, evidences are scarce to show the effects of extracellular factors from one carcinoma microenvironment upon growth and survival of another carcinoma. Methodology: To address the above issue, we have selected excised breast carcinoma tissue samples and in vitro grown MCF-7 sources of extracellular factors and tested their effects to evaluate growth and proliferation inhibitory potential against a cervical carcinoma cell line HeLa. Results: Data from the in vitro experiments like Trypan blue dye exclusion, MTT assay, cell cycle assay and annexin V/PI staining lead us to suggest that the extracellular factors collected from the culture medium of in vitro grown MCF-7 and excised breast carcinoma tissue play an apoptosis inducing and cell cycle arrest role in HeLa. In these in vitro experiments, we detected the presence of up to 40-50% apoptotic cell death in HeLa cells and increase in G2-M cell cycle phase from 11%-25% due to treatment with extracellular factors from human breast carcinoma cells. Discussion and Conclusion: These observations are novel and suggest that extracellular factors from breast carcinoma play an apoptosis inducing and growth inhibitory role upon on HeLa cells. This study can also support the concept of cancer cachexia and a possible hypothesis for rare chance of synchronous two or more primary tumor in a single patient.

Potential of Taming MicroRNA on Driver Seat to Control Mitochondrial Horses in Breast Carcinoma.

Breast cancer among women is one of the most common carcinomas worldwide. Compared to developed countries, the breast cancer cases reported in India have boosted rapidly. At the same time, alarming statistics show that ratio of mortality cases over the total incidences is significantly high in comparison to developed world (Global Heath Estimates, WHO 2015). In recent times, several oncogenic signaling pathways have shown convergent effects on various types of cancer cell metabolism including breast cancer leading to tumor development. In 1931, German biochemist Otto Warburg revealed that cancer cells burn sugar (glycolysis) differently than normal cells. Cancer cells prefer to burn sugar over energy rich fats even when cellular oxygen conditions favor mitochondrial fat burning. Further, Warburg hypothesized that cancer is caused by mitochondrial dysfunction forcing the cells to use aerobic glycolysis instead of oxidative phosphorylation (OXPHOS). MicroRNAs (miRNAs) are critical classes of small ~22 nt non-coding endogenous RNAs implicated in gene expression regulation. To date, miRNAs have shown to regulate many cellular metabolic pathways critical for breast carcinoma patho-physiology. There is common consent that miRNAs dedicated to mitochondria and cellular metabolism have profound positive effects on breast carcinoma survival and metastasis. Therefore, in future there is huge scope for identification of miRNA types playing as a driver in mitochondria for breast tumor development. Further, several strategies to taming as well as knocking down these miRNA in breast tumor would be one of the fascinating approaches in medical sciences and cancer therapy. Here, we review updated scientific findings and possible therapeutic interventions with reference to miRNAs, mitochondria, cellular metabolism and breast carcinoma.

Nitric Oxide Down-Regulates Topoisomerase I and Induces Camptothecin Resistance in Human Breast MCF-7 Tumor Cells.

Camptothecin (CPT), a topoisomerase I poison, is an important drug for the treatment of solid tumors in the clinic. Nitric oxide (·NO), a physiological signaling molecule, is involved in many cellular functions, including cell proliferation, survival and death. We have previously shown that ·NO plays a significant role in the detoxification of etoposide (VP-16), a topoisomerase II poison in vitro and in human melanoma cells. ·NO/·NO-derived species are reported to modulate activity of several important cellular proteins. As topoisomerases contain a number of free sulfhydryl groups which may be targets of ·NO/·NO-derived species, we have investigated the roles of ·NO/·NO-derived species in the stability and activity of topo I. Here we show that ·NO/·NO-derived species induces a significant down-regulation of topoisomerase I protein via the ubiquitin/26S proteasome pathway in human colon (HT-29) and breast (MCF-7) cancer cell lines. Importantly, ·NO treatment induced a significant resistance to CPT only in MCF-7 cells. This resistance to CPT did not result from loss of topoisomerase I activity as there were no differences in topoisomerase I-induced DNA cleavage in vitro or in tumor cells, but resulted from the stabilization/induction of bcl2 protein. This up-regulation of bcl2 protein in MCF-7 cells was wtp53 dependent as pifithrine-α, a small molecule inhibitor of wtp53 function, completely reversed CPT resistance, suggesting that wtp53 and bcl2 proteins played important roles in CPT resistance. Because tumors in vivo are heterogeneous and contaminated by infiltrating macrophages, ·NO-induced down-regulation of topoisomerase I protein combined with bcl2 protein stabilization could render certain tumors highly resistant to CPT and drugs derived from it in the clinic.

Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.

Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3.